TY - JOUR
T1 - A gp130-Src-YAP module links inflammation to epithelial regeneration
AU - Taniguchi, Koji
AU - Wu, Li Wha
AU - Grivennikov, Sergei I.
AU - De Jong, Petrus R.
AU - Lian, Ian
AU - Yu, Fa Xing
AU - Wang, Kepeng
AU - Ho, Samuel B.
AU - Boland, Brigid S.
AU - Chang, John T.
AU - Sandborn, William J.
AU - Hardiman, Gary
AU - Raz, Eyal
AU - Maehara, Yoshihiko
AU - Yoshimura, Akihiko
AU - Zucman-Rossi, Jessica
AU - Guan, Kun Liang
AU - Karin, Michael
N1 - Funding Information:
Acknowledgements We thank D. Pan and S. Akira for Yapfl/fl and Stat3fl/fl mice, respectively. We also thank D. L. Gumucio for a plasmid containing the 12.4-kb villin promoter, T. Sato, H. Clevers and Y. Hippo for protocols describing intestinal organoid culture, C. Kuo for R-spondin1-producing cells, D. Huszar for AZD1480, F. Schaper for plasmids,L.Eckmannforadvice,A.Umemura,H.Nakagawa,H.Ogata,E.J.Park,G.Y.Yu, J. Font-Burgada, D. Dhar, J. Kim and E. Seki for providing liver samples, J. Zhao, T. Meerloo, Y. Jones, L. Gapuz, R. Ly, N. Varki, D. Aki, N. Hiramatsu, T. Moroishi, Y. Endo, H. Nishinakamura, A. Chang and T. Lee for technical advice and assistance, and Cell Signaling, Santa Cruz Biotechnology and GeneTex for antibodies. This work was supported by Postdoctoral Fellowship for Research Abroad and Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science, a Uehara Memorial Foundation Fellowship, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Kanae Foundation for the Promotion of Medical Science to K.T.; a traveling grant NSC-101-2918-I-006-005 and a research grant NSC-103-2320-B-006-032 by National Science Council of Taiwan to L.-W.W.; NIH R00DK088589, FCCC-Temple University Nodal grant, AACR-Landon Innovator Award in Tumor Microenvironment, and the Pew Scholar in Biomedical Sciences Program for S.I.G.; a CCFA fellowship (RFA2927) to P.R.d.J.; Croucher Foundation and China Postdoctoral Science Foundationto K.W.; by the Research Service of the Departmentof Veterans Affairs to S.B.H.; by the NIH and the UCSD Digestive Disease Research Center Grant to J.T.C. and W.J.S.; by the NIH EY022611 and CA132809 to K.-L.G.; and by the NIH CA118165-09 and AACR to M.K., who is an American Cancer Society Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.
Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/3/5
Y1 - 2015/3/5
N2 - Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
AB - Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
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U2 - 10.1038/nature14228
DO - 10.1038/nature14228
M3 - Article
C2 - 25731159
AN - SCOPUS:84924328294
SN - 0028-0836
VL - 519
SP - 57
EP - 62
JO - Nature
JF - Nature
IS - 7541
ER -
